One of the major rate limiting steps in protein folding is the thiol:disulfide exchange that is necessary for correct protein assembly. Although incubation of reduced, unfolded proteins in buffers with defined ratios of oxidized and reduced thiols can lead to native conformation, the rate of folding is slow, and the attainment of native conformation decreases proportionately with protein size and number of cysteines. Certain cellular compartments such as the endoplasmic reticulum of eukaryotes and the periplasmic space of prokaryotes are maintained in a more oxidized state than the surrounding cytosol. Correct disulfide formation can occur in these compartments, but it occurs at a rate that is insufficient for normal cell processes and inadequate for synthesizing secreted proteins. The protein disulfide isomerases (PDIs), thioredoxins and glutaredoxins, are able to catalyze the formation of disulfide bonds and regulate the redox environment in cells to enable the necessary thiol:disulfide exchanges.
Each of these proteins has a somewhat different function, but all belong to a group of disulfide-containing redox proteins that contain a conserved active-site sequence and are ubiquitously distributed in eukaryotes and prokaryotes. Protein disulfide isomerases are found in the endoplasmic reticulum of eukaryotes and in the periplasmic space of prokaryotes. They function by exchanging their own disulfide for a thiol in a folding peptide chain. In contrast, the reduced thioredoxins and glutaredoxins are generally found in the cytoplasm and function by directly reducing disulfides in the substrate proteins (Holmgren, A. (1985) Annu. Rev. Biochem. 54:237-271).
PDIs not only facilitate disulfide formation, but they also regulate and participate in a wide variety of physiological processes. The thioredoxin system serves, for example, as a hydrogen donor for ribonucleotide reductase and controls the activity of enzymes by redox reactions. Mammalian thioredoxin acts as hydrogen donor for ribonucleotide reductase and methionine sulfoxide reductase, facilitates refolding of disulfide-containing proteins, and activates the glucocorticoid or interleukin-2 receptors. It also modulates the DNA binding activity of some transcription factors either directly (TFIIIC, BZLF 1, and NF-kB) or indirectly (AP-1) through the nuclear factor Ref-1. The importance of the redox regulation of transcription factors is exemplified by the v-fos oncogene where a point mutation of the thioredoxin-modulated cysteine results in constitutive activation of the AP-1 complex. Thioredoxin can be secreted by cells using a leaderless pathway and stimulate the proliferation of lymphoid cells, fibroblasts, and a variety of human solid tumor cell lines. Furthermore, thioredoxin is an essential component of the early pregnancy factor, inhibits human immunodeficiency virus expression in macrophages, can reduce H.sub.2 O.sub.2, scavenge free radicals, and protect cells against oxidative stress (Abate, C. et al., (1990) Science 249:1157-1161; Rosen, A. et al. (1995) Int. Immunol. 7:625-633; Wollman, E. E. et al (1988) J. Biol. Chem. 263:15506-15512; Tagaya, Y. et al (1989) EMBO J. 8:757-764; Yamauchi, A. et al (1992) Mol. Immunol. 29:263-270; Newman, G. W. (1994) J. Expt. Med. 180:359-363; and Makino, Y. (1996) J. Clin. Invest. 98:2469-2477).
The discovery of thioredoxin-like protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of cancer, inflammatory disorders, and viral infections.